Phenylene-bis-dithiocarbamic acid esters

ABSTRACT

ANTHELMINITICALLY ACTIVE PHENYLENE-BIS-DITHIOCARBAMIC ACID ESTERS OF THE FORMULA   BIS(R3-CH2-S-C(=S)-NH-),R1,R2-BENZENE   IN WHICH R1 AND R2 ARE EQUAL OR DIFFERENT AND REPRESENT HYDROGEN, HALOGEN, ALKYL OR ALKOXYL HAVING FROM 1 TO 6 CARBON ATOMS AND R3 IS PYRIDYL, QUINOLYL OR ISOQUINOLYL WHICH MAY BE SUBSTITUTED BY ONE OR MORE ALKYL RADICALS HAVING FROM 1 TO 6 CARBON ATOMS. A PROCESS FOR THEIR PREPARATION.

United States Patent 01 iice 3,812,131 Patented May 21, 1974 US. Cl.260-283 S 3 Claims ABSTRACT OF THE DISCLOSURE Anthelmintically activephenylene-bis-dithiocarbamic acid esters of the formula in which R and Rare equal or diiferent and represent hydrogen, halogen, alkyl or alkoxyhaving from 1 to 6 carbon atoms and R is pyridyl, quinolyl orisoquinolyl which may be substituted by one or more alkyl radicalshaving from 1 to 6 carbon atoms. A process for their preparation.

This is a division of application Ser. No. 70,485 filed Sept. 8, 1970,now US Pat. 3,676,446.

The present invention relates to bis-dithiocarbamic acid esters of thegeneral formula I in which R, and R are equal or dilferent and representhydrogen, halogen, alkyl or alkoxy having from 1 to 6 carbon atoms and Ris, quinolyl or isoquinolyl which may be substituted by one or morealkyl radicals having from 1 to 6 carbon atoms.

The present invention further relates to a process for the preparationof the said compounds which comprises reacting a water-soluble salt of abis-dithiocarbamic acid of the formula II S eat-HQ H in which Xrepresents one cation-equivalent with a reactive ester of an alcohol ofthe formula III By the term reactive esters there are understoodespecially chlorides, bromides and iodides, further, for example,sulfonates, methylsulfonates (mesylates) and toluenesulfonates(tosylates). The following substances may thus be used as startingmaterials: 2-chloromethylquinoline, 2-bromomethylquinoline,3-chloromethylquinoline, 4-chloromethylquinoline, 1chloromethylisoquinoline, 3-chloromethylisoquinoline,4-chloromethylisoquinoline, 1 chloromethyl-4-methylisoquinoline. Thesecompounds are advantageously used as hydrochlorides and, at thebeginning of the reaction, set free by addition of the equivalent amountof base.

The salts of the phenylene-bis-dithiocarbamic acid esters of the formulaII can be obtained by the method described by van der Kerk et a1. (Rec.74, 1268 (1955)). Advantageously, the alkaline, alkaline earth orammonium salts as well as the salts of organic bases, especiallytertiary amines, are used.

The reaction is advantageously carried out as follows: a compound of theformula III dissolved in a watermiscible solvent, for example acetone,alcohol, tetrahydrofurane, dioxane, acetonitrile, formamide,dimethylformamide, or dimethylsulfoxide, is added to the aqueoussolution of a phenylene-bis-dithiocarbamate. The reaction product, whichprecipitates after a short time, is separated and purified by washing orreprecipitating from suitable solvents. According to another operationmode, it is also possible to prepare in situ thephenylene-bisdithiocarbamate from the corresponding phenylenediamine,carbon disulfide and alkali or ammonia and then to react it immediatelywith a halogen derivative of a compound of the formula III. The reactiontemperature should be between about 0 and 60 C., room temperature beingpreferred.

The phenylene-bis-dithiocarbamic acid esters of the present inventionare chemotherapeutically active and suitable for fighting helminthicdiseases in mammals. They are especially active against several speciesof cat liver fluke (Opisthorchis felineus, Opisthorchis viverini,Clonorchis sinensis), and against which up to now no specificchemotherapeutic agent exists. Liver fluke diseases are an importantproblem in many countries of Asia. The chemotherapeutic tests werecarried out using gold hamsters which had been infected withOpisthorchis felineus. The examined compounds were applied orally to theanimals for three to five consecutive days (once each day). The successof the treatment was judged by examination of the excrements foregg-secretion as well as by dissection.

The invention compounds are advantageously used for the production oforally applicable preparations for the treatment of helmintic diseases.

Suitable medical preparations are for example capsules, dragees, tabletsetc., which may contain, in addition to the invention compounds, theusual auxiliaries and carriers. It is also possible to combine theproducts of the invention with other chemotherapeutic agents. The doseof the active substance to be used depends on the compound incorporatedas active ingredient and on the desired eifect.

The following example illustrate the invention.

EXAMPLE I (a) 1,3-phenylene-bis-dithiocarbamic acid quinolyl-2- methylester 7.35 g. (0.025 mol) of the ammonium salt of1,3-phenylene-bis-dithiocarbamic acid were dissolved in 200 cc. ofwater, and a solution of 5 g. of sodium bicarbonate and 10.7 g. of2-chloromethylquinoline-hydrochloride in ml. of methanol was added whilestirring at room temperature. The precipitate formed after some time wassuction-filtered, washed with acetone and ether and dried in vacuo. 5 g.(37%) of 1,3-pheny1ene-bis-dithiocarbamic acid quinolyl-2-methyl ester,decomposition point 128- 129 C. were obtained.

Quantitative analysis: C H N S (M.W. 542.8). Calculated: C, 61.97; H,4.09; N, 10.32; S, 23.64. Found: C, 61.9; H, 4.1-, N, 10.6; S, 23.4.

In an analogous manner there was obtained: (b) 2-methyl-l,4-phenylene-bis-dithiocarbamic acid quinolyl-Z- methyl ester,decomposition beginning at 133 C.

What is claimed is:

1. Bis-dithiocarbamic acid ester of the formula I in which R and R areequal or different and are hydro- 4 gen, halogen, methyl or methoxy, andR is quinolyl or isoquinolyl, which may be substituted by methyl.

2. 1,3 phenylene-bis-dithiocarbamic acid quinolyl-2- methyl ester.

3. Z-methyl-l,4-phenylene-bis-dithiocarbamic acid quino1yl-2-methylester.

References Cited UNITED STATES PATENTS 3,308,128 3/1967 Robinson 260-283S 3,391,146 7/1968 Godfrey 260-283 S 3,705,151 12/ 1972 Weber 260-283 SDONALD DAUS, Primary Examiner US. Cl. X.R.

